Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Department of Nutritional Science, Fu Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City, 24205, Taiwan.
Sci Rep. 2021 Jan 13;11(1):1239. doi: 10.1038/s41598-020-80519-3.
Enzalutamide (ENZ) is an important drug used to treat castration-resistant prostate cancer (CRPC), which inhibits androgen receptor (AR) signaling. Previous study showed that 3,3'-diindolylmethane (DIM) is an AR antagonist that also inhibits Wnt signaling and epithelial-mesenchymal transition (EMT). To investigate whether combined treatment with ENZ and DIM can overcome ENZ resistance by regulating Wnt signaling to inhibit AR signaling and EMT in ENZ-resistant prostate cancer cells, 22Rv1 cells were cultured in normal medium and treated with ENZ, DIM, and DIM with ENZ. Exposure of ENZ-resistant cells to both DIM and ENZ significantly inhibited cell proliferation without cytotoxicity and invasion in comparison with the control. DIM significantly increased the E-cadherin expression and inhibited the expressions of Vimentin and Fibronectin, subsequently inhibiting EMT. Co-treatment with ENZ and DIM significantly increased the expressions of GSK3β and APC and decreased the β-catenin protein expression, causing inhibition of Wnt signaling and AR expression, it also significantly decreased the AR-v7 expression and down-regulated AR signaling. Via suppression of Wnt and AR signaling, co-treatment increased the E-cadherin and decreased the Vimentin and Fibronectin RNA and protein expressions, then inhibited EMT. Co-treatment with DIM and ENZ regulated Wnt signaling to reduce not only the AR expression, but also the AR-v7 expression, indicating suppression of EMT that inhibits cancer cell proliferation, invasion and migration to ameliorate ENZ resistance.
恩扎卢胺（ENZ）是一种用于治疗去势抵抗性前列腺癌（CRPC）的重要药物，它可抑制雄激素受体（AR）信号。先前的研究表明，3,3'-二吲哚甲烷（DIM）是一种 AR 拮抗剂，它还抑制 Wnt 信号和上皮-间充质转化（EMT）。为了研究联合使用 ENZ 和 DIM 是否可以通过调节 Wnt 信号来抑制 AR 信号和 EMT，从而克服 ENZ 耐药性，在 22Rv1 细胞中培养正常培养基并分别用 ENZ、DIM 和 ENZ+DIM 处理。与对照组相比，ENZ 耐药细胞暴露于 DIM 和 ENZ 两者中时，细胞增殖明显受到抑制，且无细胞毒性和侵袭性。与对照组相比，DIM 显著增加了 E-钙黏蛋白的表达，抑制了波形蛋白和纤连蛋白的表达，从而抑制了 EMT。ENZ 和 DIM 的联合治疗显著增加了 GSK3β和 APC 的表达，降低了 β-连环蛋白蛋白的表达，从而抑制了 Wnt 信号和 AR 的表达，还显著降低了 AR-v7 的表达并下调了 AR 信号。通过抑制 Wnt 和 AR 信号，联合治疗增加了 E-钙黏蛋白的表达，降低了波形蛋白和纤连蛋白的 RNA 和蛋白表达，从而抑制了 EMT。ENZ 和 DIM 的联合治疗通过调节 Wnt 信号不仅降低了 AR 的表达，还降低了 AR-v7 的表达，表明抑制 EMT 抑制了癌细胞的增殖、侵袭和迁移，从而改善了 ENZ 耐药性。
